The candidate is a board certified clinical neuropsychologist with prior research experience examining cognitive functioning of patients with chronic hepatitis C. The research environment includes ample office and laboratory space, computers and testing equipment, administrative and technical personnel, and strong institutional support for devoting at least 75% time to career development in conducting patient-oriented research. The purpose of this application is to provide the candidate with the necessary training in viral neuroimmunology to become an independent researcher capable of investigating the relationship between the immune response and cognitive functioning. Career development will include both didactic and "hands on" training in viral neuroimmunology and research methodology associated with measurement of cytokines. The long-term goal is for the candidate to develop a programmatic line of research that will contribute to the limited understanding of how the immune system influences cognitive functioning. Specific Aims of this project are: 1) to test the hypothesis that higher levels of interferon-alpha (IFN-a), a proinflammatory cytokine, are associated with cognitive dysfunction in patients with chronic hepatitis C infection (CMC) as measured by neuropsychological tests, and 2) to test the hypothesis that higher levels of IFN-a are associated with cognitive dysfunction as indicated by inhibition of complex motor pathways in patients with CMC measured by image-guided, robotically positioned transcranial magnetic stimulation surface electromyography (irTMS-sEMG). CMC infection is associated with significant morbidity and mortality, including mood and cognitive disturbances. To complicate matters further, IFN-a, the primary treatment for CHC, also is associated with mood and cognitive disturbances. While much research has focused on mood disturbances associated with IFN-a therapy, far less attention has been paid to associated cognitive difficulties. In this study, patients with CHC will undergo neuropsychological testing, psychiatric assessment, cytokine measurement, and irTMS-sEMG within 1 month of beginning IFN-a therapy and again after 12 weeks of IFN-a therapy. Changes in cognitive functioning over time will be compared to that of a healthy comparison group tested over the same time interval. Levels of IFN-a and other cytokines in serum also will be examined and related to cognitive functioning. Knowledge gained by examining these relationships will increase understanding of how the immune response affects thinking abilities of patients with CHC and may provide insights into treatments for thinking problems. Additionally, these relationships may be true in patients with other chronic diseases that affect thinking, such as Alzheimer's disease and systemic lupus erythematosus, leading to possible treatments for these patients, as well.